Inherited human ITK deficiency impairs IFN-γ immunity and underlies tuberculosis

• DOI: 10.1084/jem.20220484
• Publication Date: 2022-11-03T13:54:15Z
• Authors: Masato Ogishi; Rui Yang; Rémy Rodriguez; Dominic P. Golec; Emmanuel Martin; Quentin Philippot; Jonathan Bohlen; Simon J. Pelham; Andrés Augusto Arias; Taushif Khan; Manar Ata; Fatima Al Ali; Flore Rozenberg; Xiao-Fei Kong; Maya Chrabieh; Candice Laine; Wei-Te Lei; Ji Eun Han; Yoann Seeleuthner; Zenia Kaul; Emmanuelle Jouanguy; Vivien Béziat; Leila Youssefian; Hassan Vahidnezhad; V. Koneti Rao; Bénédicte Neven; Claire Fieschi; Davood Mansouri; Mohammad Shahrooei; Sevgi Pekcan; Gulsum Alkan; Melike Emiroğlu; Hüseyin Tokgöz; Jouni Uitto; Fabian Hauck; Jacinta Bustamante; Laurent Abel; Sevgi Keles; Nima Parvaneh; Nico Marr; Pamela L. Schwart...; Sylvain Latour; Jean-Laurent Casa...; Stéphanie Boisson...
• Keywords: 0301 basic medicine; Cytotoxic T cell; Receptors, Antigen, T-Cell, alpha-beta; Human Inborn Errors; Immunology; 610; Dermatology; Thymus Gland; Lymphocytosis; Article; Mice; Interferon-gamma; 03 medical and health sciences; In vitro; T-Lymphocyte Subsets; Genetic Basis of Neutropenia Disorders; Biochemistry, Genetics and Molecular Biology; Receptors; 616; Medicine and Health Sciences; Genetics; T lymphocyte; Animals; Humans; Tuberculosis; Immunodeficiency; Biology; alpha-beta; Immunology and Microbiology; gamma-delta; 0303 health sciences; Interferon-? Pathway Defects; Genetic Basis of Primary Immunodeficiency Disorders; FOS: Clinical medicine; Lymphocytopenia; Immunity; Life Sciences; T cell; Receptors, Antigen, T-Cell, gamma-delta; CD8; T-Cell; 3. Good health; [SDV] Life Sciences [q-bio]; Immune system; Antigen; FOS: Biological sciences; Lymphocyte; Natural Killer Cells in Immunity

Inborn errors of IFN-γ immunity can underlie tuberculosis (TB). We report three patients from two kindreds without EBV viremia or disease but with severe TB and inherited complete ITK deficiency, a condition associated with severe EBV disease that renders immunological studies challenging. They have CD4+ αβ T lymphocytopenia with a concomitant expansion of CD4−CD8− double-negative (DN) αβ and Vδ2− γδ T lymphocytes, both displaying a unique CD38+CD45RA+T-bet+EOMES− phenotype. Itk-deficient mice recapitulated an expansion of the γδ T and DN αβ T lymphocyte populations in the thymus and spleen, respectively. Moreover, the patients’ T lymphocytes secrete small amounts of IFN-γ in response to TCR crosslinking, mitogens, or forced synapse formation with autologous B lymphocytes. Finally, the patients’ total lymphocytes secrete small amounts of IFN-γ, and CD4+, CD8+, DN αβ T, Vδ2+ γδ T, and MAIT cells display impaired IFN-γ production in response to BCG. Inherited ITK deficiency undermines the development and function of various IFN-γ–producing T cell subsets, thereby underlying TB.